This invention relates to substances which exhibit an antagonism to binding of nociceptin to nociceptin receptor ORL1 (Opioid receptor-like-1 receptor).
Compounds which inhibit binding of nociceptin to nociceptin receptor ORL1 are useful as analgesics against diseases accompanied with pain such as cancerous pain, postoperative pain, migraine, gout, chronic rheumatism, chronic pain and neuralgia; relievers against tolerance to narcotic analgesic represented by morphine; relievers against dependence on narcotic analgesic represented by morphine or against addiction; analgesic enhancers; antiobestic or appetite suppressors; treating or prophylactic agents for cognitive impairment and dementia/amnesia in aging, cerebrovascular diseases and Alzheimer's disease; agents for treating developmental cognitive abnormality in attention deficit, hyperactivity disorder and learning disability; remedy for schizophrenia; agents for treating neurodegenerative diseases represented by Parkinsonism and chorea; anti-depressant or treating agents for affective disorder; treating or prophylactic agents for diabetes insipidus; treating or prophylactic agents for polyuria; and remedy for hypotension and the like.
1. Field of the Invention
Nociceptin (the same substance as orphanin FQ) is a peptide consisting of 17 amino acid units having a similar structure to that of opioid peptide. Nociceptin has activity on reactivity against nociceptive stimulation, appetite stimulating activity, activity for reducing space learning ability, antagonism against analgesic action of classic opiate agonists, dopamine release inhibitory action, water diuresis action, vasodilative action and systemic blood pressure-lowering action, and it is considered to take part in intracerebral controlling of pain, appetite and memory learning through a nociceptin receptor ORL1 (cf. Nature, 377, 532 (1995); Society for Neuroscience, 22, 455 (1996); NeuroReport, 8, 423 (1997); Eur. J. Neuroscience, 9, 194 (1997); Neuroscience, 75, 1 (1996); ibid., 333 (1996); Life Sciences, 60, PL15 (1997); ibid., PL141 (1997); Proceedings for National Academy of Sciences, 94, 14858 (1997)).
Further, it is known that morphine tolerance is reduced or memory and learning ability are improved in knockout mice in which expression of nociceptin receptor ORL1 is inhibited (cf. Neuroscience Letters, 237, 136 (1997); Nature, 394, 577 (1998)).
It has also been reported that nociceptin itself induces symptoms resembling withdrawal symptoms observed with morphine addicts, and that non-peptide nociceptin receptor antagonist improves morphine tolerance, dependence and symptoms resembling withdrawal symptoms (cf. Psychopharmacology, 151, 344-350 (2000); Journal of Neuroscience, 20, 7640 (2000)).
On the other hand, nociceptin protein precursor-defective mice are reported to show behaviors resembling anxiety and changes in stress response (cf. Proceedings for National Academy of Sciences, 96, 10444 (1999)).
Hence substances which specifically inhibit binding of nociceptin to nociceptin receptor ORL1 are useful as analgesics against diseases accompanied with pain such as cancerous pain, postoperative pain, migraine, gout, chronic rheumatism, chronic pain and neuralgia; relievers against tolerance to narcotic analgesic represented by morphine; relievers against dependence on narcotic analgesic represented by morphine or against addiction; analgesic enhancers; antiobestic or appetite suppressors; treating or prophylactic agents for cognitive impairment and dementia/amnesia in aging, cerebrovascular diseases and Alzheimer's disease; agents for treating developmental cognitive abnormality in attention deficit, hyperactivity disorder and learning disability; remedy for schizophrenia; agents for treating neurodegenerative diseases represented by Parkinsonism and chorea; anti-depressant or treating agents for affective disorder, treating or prophylactic agents for diabetes insipidus; treating or prophylactic agents for polyuria; and remedy for hypotension and the like.
2. Description of Related Art
International Publication WO98/54168 or J. Med. Chem. 5061-5063 (1999) disclose compounds having antagonism to binding of nociceptin to nociceptin receptor ORL1. In particular, the compound of the following formula (A)
(hereinafter referred to as “Compound A”) is disclosed as having excellent selective antagonism to binding of nociceptin to nociceptin receptor. Patent literature 1: International Publication WO98/54168. Non-patent literature 1: J. Med. Chem., 1999, 5061-5063